具有免疫调节功能的相转变纳米液滴增强温和磁热疗抑制肿瘤增殖和转移。

BACKGROUND: Magnetic hyperthermia (MHT)-mediated thermal ablation therapy has promising clinical applications in destroying primary tumours. However, traditional MHT still presents the challenges of damage to normal tissues adjacent to the treatment site and the destruction of tumour-associated antigens due to its high onset temperature (> 50 °C). In addition, local thermal ablation of tumours often exhibits limited therapeutic inhibition of tumour metastasis. RESULTS: To address the above defects, a hybrid nanosystem (SPIOs + RPPs) was constructed in which phase transition nanodroplets with immunomodulatory capabilities were used to potentiate supermagnetic iron oxide nanoparticle (SPIO)-mediated mild MHT (< 44 °C) and further inhibit tumour proliferation and metastasis. Magnetic-thermal sensitive phase-transition nanodroplets (RPPs) were fabricated from the immune adjuvant resiquimod (R848) and the phase transition agent perfluoropentane (PFP) encapsulated in a PLGA shell. Because of the cavitation effect of microbubbles produced by RPPs, the temperature threshold of MHT could be lowered from 50℃ to approximately 44℃ with a comparable effect, enhancing the release and exposure of damage-associated molecular patterns (DAMPs). The exposure of calreticulin (CRT) on the cell membrane increased by 72.39%, and the released high-mobility group B1 (HMGB1) increased by 45.84% in vivo. Moreover, the maturation rate of dendritic cells (DCs) increased from 4.17 to 61.33%, and the infiltration of cytotoxic T lymphocytes (CTLs) increased from 10.44 to 35.68%. Under the dual action of mild MHT and immune stimulation, contralateral and lung metastasis could be significantly inhibited after treatment with the hybrid nanosystem. CONCLUSION: Our work provides a novel strategy for enhanced mild magnetic hyperthermia immunotherapy and ultrasound imaging with great clinical translation potential.

背景：磁热疗（MHT）介导的热消融治疗在破坏原发性肿瘤方面具有有前景的临床应用。然而，由于其起始温度较高（>50°C），传统的 MHT 仍然存在对治疗部位附近正常组织的损伤和肿瘤相关抗原破坏的挑战。此外，肿瘤的局部热消融往往对肿瘤转移的治疗抑制作用有限。

结果：为了解决上述缺陷，构建了一种混合纳米系统（SPIOs+RPPs），其中具有免疫调节能力的相变纳米液滴用于增强超顺磁性氧化铁纳米颗粒（SPIOs）介导的温和 MHT（<44°C），并进一步抑制肿瘤增殖和转移。磁热敏感相变纳米液滴（RPPs）由免疫佐剂瑞喹莫德（R848）和包裹在 PLGA 壳中的相变剂全氟戊烷（PFP）制成。由于 RPPs 产生的微泡的空化效应，MHT 的温度阈值可以从 50°C 降低到约 44°C，效果相当，增强了损伤相关分子模式（DAMPs）的释放和暴露。细胞膜上钙网蛋白（CRT）的暴露增加了 72.39%，体内高迁移率族蛋白 B1（HMGB1）的释放增加了 45.84%。此外，树突状细胞（DCs）的成熟率从 4.17%增加到 61.33%，细胞毒性 T 淋巴细胞（CTLs）的浸润从 10.44%增加到 35.68%。在温和 MHT 和免疫刺激的双重作用下，用混合纳米系统治疗后，对侧和肺转移可以得到显著抑制。

结论：我们的工作为增强温和的磁热免疫治疗和超声成像提供了一种新的策略，具有很大的临床转化潜力。